Evaluating the influence of vaccine archetypes and epidemiological conditions on clinical trial metrics for tuberculosis vaccine candidates

Abstract

Background. Conducting tuberculosis vaccine trials in high-transmission settings offers potential gains in efficiency, yet the impact of repeated exposure in the presence of incomplete (“leaky”) protection on measured vaccine efficacy is uncertain and could result in a potentially effective vaccine to be incorrectly deemed ineffective. We aimed to evaluate the effect of vaccine characteristics and epidemiological context on estimates of vaccine efficacy and requisite sample size for tuberculosis vaccine trials. Methods. We simulated clinical trials of hypothetical tuberculosis vaccines using a stochastic compartmental model of tuberculosis natural history. We considered vaccines that confer “leaky” (50% per-exposure reduction) versus “all-or-none” protection against infection and/or disease that were evaluated in QuantiFERON Gold Plus (QFT) positive, negative or mixed populations with 2% (medium burden; incidence 400 per 100,000), 5% (high burden; 800 per 100,000) or 50% (very high burden; 4500 per 100,000) annual risk of infection (ARI), including protection against infection alone. We compared estimates of vaccine efficacy and statistical power to detect differences according to sample size for each vaccine archetype and epidemiologic setting. Findings. Simulated trials of vaccines protecting against disease, alone or with protection against infection, gave comparable estimates of efficacy across epidemiological settings, whether all-or-none or leaky. The largest reduction was for a leaky vaccine protecting against both infection and disease in QFT negative participants, whose efficacy fell from 75% at medium ARI to 67% at very high ARI (relative reduction 11%). A vaccine acting only by preventing infection fell further, from 50% to 36% (28%). Trials at very high ARI could nonetheless achieve 90% power with 80-96% fewer participants than at medium ARI. Interpretation. While vaccines conferring leaky protection against infection and disease tested in settings with very high ARI could modestly underestimate efficacy, trials could be adequately powered with a fraction of the sample size in such settings. Further, trials could enroll a mixture of QFT negative and positive individuals, increasing generalizability.